key: cord-0920991-yv04ijsm
authors: Ceccarelli, Giancarlo; Scagnolari, Carolina; Pugliese, Francesco; Mastroianni, Claudio M; d'Ettorre, Gabriella
title: Probiotics and COVID-19
date: 2020-07-13
journal: Lancet Gastroenterol Hepatol
DOI: 10.1016/s2468-1253(20)30196-5
sha: ef50d78ec68e9dbf5cc3d79296cdd1d2b591f7ba
doc_id: 920991
cord_uid: yv04ijsm

nan

"modest efficacy". 1 The odds ratio in the cited Cochrane meta-analysis is 0·53 (95% CI 0·37-0·76). 4 We believe that the efficacy of a treatment that leads to twice as great a reduction in the number of cases is far from modest. The potential for probiotics to reduce the risk and severity of viral respiratory tract infections is supported by clinical and experimental studies on influenza, rhinovirus, and respiratory syncytial virus. 2 Although none of these effects have been tested with SARS-CoV-2, some probiotic stains do have antiviral activity against other coronaviruses. 2 Given the importance of strain-to-strain differences, the selection of probiotics for testing needs to made on the basis of documented attributes. Mak and colleagues mention that the rationale for using probiotics in COVID-19 is based on indirect evidence. 1 This assertion is true for all interventions in the context of this novel disease. Ideally, preventive and therapeutic interventions should be tested in randomised controlled trials before implementation in clinical practice. In a pandemic affecting millions of people, disregarding practices that are not supported by solid evidence against this specific pathogen is not realistic. Clinicians have adopted a more pragmatic approach, and issued recommendations based on evidence from other viral infections, sepsis, and general intensive care management. 5 Currently, there is no evidence from randomised controlled trials that any medication can prevent or improve the outcomes of COVID-19, and there are hundreds of ongoing trials of antivirals, immune-modulating agents, convalescent plasma, and steroids. On the basis of limited evidence showing that Bacillus Calmette-Guérin (BCG) vaccination provides heterologous protection against respiratory tract infections, randomised trials have been launched to assess whether BCG vaccination can reduce the incidence and severity of COVID-19. 6 We propose that well documented probiotic strains deserve the same level of interest, and of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has wider implications.

SARS-CoV-2 has been postulated to affect gut inflammation both directly and indirectly, infecting intestinal epithelial cells through the angiotensin-converting enzyme 2 (ACE2) receptor and transmembrane protease serine 2, and inducing proinflammatory chemokine and cytokine release. 2, 3 Recent studies suggest that SARS-CoV-2 instigates an acute intestinal inflammatory response, highlighted in laboratory tests by elevated levels of faecal calprotectin and serum interleukin-6, and clinically evidenced by diarrhoea. 2 Although gastrointestinal disorders are frequent in COVID-19, nothing is known regarding the ability of SARS-CoV-2 to affect the host microbial flora. However, previous studies have shown that ACE2 expressed in the intestinal epithelium regulates the ecology of the gut microbiome through intestinal amino acid homoeostasis 4 and that ACE2 receptors are markedly downregulated by the entry of SARS-CoV-2 into cells through membrane fusion. 5 The intestinal downregulation of ACE2 can consequently lead to an altered microbiota that confers susceptibility to inflammation of the gut. [4] [5] [6] Moreover, other coronaviruses, such as the porcine epidemic diarrhoea virus, are able to directly cause microbial dysbiosis, with decreases in the proportion of beneficial bacteria and increases in harmful bacteria. 7 Given this evidence, bacteriotherapy could represent a complementary resource for the prevention and restoration of SARS-CoV-2 intestinal mucosa damage through the modulation of gut microbiota and decreasing related inflammation. In other infections, such as HIV, in which intestinal inflammation and related microbiota impairment can affect gut epithelial barrier function, bacteriotherapy (through microbiota surface compounds and metabolites) to exist between different probiotic bacterial species and strains. Organisms therefore need to be selected in a rational manner to treat different diseases. 5 Currently, questions remain concerning which patients should receive probiotics, what is the best way to deliver probiotics, how to ensure optimal delivery, and whether there is variation in efficacy among different populations. As the world waits in semi-lockdown mode, continued scientific progress for COVID-19 prevention or treatment is highly important, and probiotics represent one option. We call for robust and well planned studies that can facilitate the identification of probiotic strains, including both well documented probiotics and novel COVID-19-specific probiotics, that might result in reduced susceptibility to COVID-19 or less severe disease. has been shown to inhibit apoptosis, regulate signalling pathways to produce cytokines, maintain intestinal epithelial homoeostasis, and allow recovery of gut mucosal health, thereby attenuating inflammation. 8, 9 We believe that studies of bacteriotherapy in SARS-CoV-2 are needed to evaluate the potential effects on intestinal mucosal inflammation and microbiome homoeostasis. Finally, products available for bacteriotherapy are not the same and have different potential effects. Thus, the conclusions of each study must be considered separately, and the results of meta-analyses that collate data obtained from studies done with different products can be misleading.

We declare no competing interests.

Department of Anaesthesia and Intensive Care Medicine (FP), and Laboratory of Virology

Probiotics and COVID-19: one size does not fit all

Faecal calprotectin indicates intestinal inflammation in COVID-19

Digestive system is a potential route of COVID-19: an analysis of single-cell coexpression pattern of key proteins in viral entry process

ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation

The pivotal link between ACE2 deficiency and SARS-CoV-2 infection

ACE2-from the reninangiotensin system to gut microbiota and malnutrition

Changes in cecal microbiota community of suckling piglets infected with porcine epidemic diarrhea virus

We thank Eric Giannoni and colleagues and Giancarlo Ceccarelli and colleagues for their comments on our Correspondence. 1 New data have since highlighted that patients with COVID-19 have an altered gut microbiome with depletion of beneficial commensals (Eubacterium ventriosum, Faecalibacterium prausnitzii, Roseburia and Lachnospiraceae taxa) and enrichment of opportunistic pathogens (Clostridium hathewayi, Actinomyces viscosus, Bacteroides nordii) during hospitalisation. 2 Importantly, gut microbiome configuration was associated with COVID-19 disease severity, and altered gut microbiota persisted even after clearance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), suggesting that the virus might inflict prolonged harm to human microbiome homoeostasis. 2 Other risk factors for severe COVID-19, including old age, obesity, and diabetes mellitus, 3 have been shown to be associated with gut dysbiosis, which might contribute to the poor prognosis of COVID-19. 4 During this crucial moment, with more than 6 million confirmed cases of COVID-19 globally, we understand that the situation is desperate, and it is not uncommon to try all alternative measures. In the absence of a vaccine or effective therapy for COVID-19, we agree that probiotics represent a complementary approach for the prevention and restoration of SARS-CoV-2-induced mucosal damage or inflammation through the modulation of gut microbiota. Probiotics exert their beneficial effects through several different mechanisms, and substantial differences appear